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Original Research |
1 Department of Radiology, University of Texas Health Science Center at San
Antonio, 7703 Floyd Curl Dr., San Antonio, TX 78229-3900.
2 Academic Informatics Services, University of Texas Health Science Center at
San Antonio, San Antonio, TX 78229-3900.
Received October 21, 2003;
accepted after revision October 2, 2004.
Address correspondence to G. D. Dodd III
(dodd{at}uthscsa.edu).
Abstract
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SUBJECTS AND METHODS. We performed 50 consecutive percutaneous radiofrequency ablation sessions on 39 patients with a total of 89 liver tumors. All patients had pre- and postablation laboratory studies and CT or MRI scans. After treatment, patients were followed for 3 weeks with a standardized questionnaire to assess for postablation symptoms. Comparisons of the presence or absence of symptoms were made for the laboratory test values, liver volumes, and pre- and postablation tumor volumes.
RESULTS. Postablation symptoms occurred in 14 of 39 (36%) patients after 17 of 50 (34%) ablation sessions. Symptoms consisted of fever (16/17), malaise (12/17), chills (6/17), delayed pain (5/17), and nausea (2/17). On average, the symptoms presented 3 days after ablation and lasted 5 days. Statistically significant (p < 0.01) predictors of symptoms were tumor volumes > 50 cm3 (4.5 cm diameter), ablated tissue volumes > 150 cm3 (6.5 cm diameter), a difference between preablation tumor volume and the volume of tissue ablated > 125 cm3, or postablation aspartate aminotransferase levels > 350 IU/L.
CONCLUSION. Approximately one third of patients undergoing percutaneous radiofrequency ablation of hepatic tumors develop delayed, transient flulike symptoms that can be treated conservatively and are significantly related to the volume of tissue ablated. Familiarity with this postablation syndrome should facilitate appropriate management of affected patients.
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Pretreatment Evaluation
All patients had a pretreatment physical examination and a full review of
systems, with results entered in the clinical chart. The following blood
chemistries were performed in all patients before treatment: WBC with
differential, RBC with volumes and differentials, hemoglobin, hematocrit,
alkaline phosphatase, total protein, calcium, serum creatinine, blood urea
nitrogen, glucose, chloride, potassium, sodium, partial thromboplastin time,
international normalized ratio, prothrombin time, and liver function
tests—aspartate aminotransferase (AST), alanine aminotransferase (ALT),
ammonia, albumin, and total bilirubin. All laboratory values were compared
with hospital standards for normal values.
Pre- and postablation helical CT scans and MRI scans of the liver were performed in 37 and two patients, respectively. Preablation scans were performed within 1 month before the ablation procedure. Postablation scans were performed within 4 hr after the ablation and every 3 months thereafter. CT scans were acquired on helical scanners (HiSpeed Advantage, GE Healthcare; and Picker PQ or PQ5000, Picker International) with 1-sec tube rotation speeds. All CT scans were performed as unenhanced and dual-phase contrast-enhanced CT scans of the entire liver, with images obtained in a cranial to caudal direction. Precontrast images were obtained as contiguous axial scans. Arterial and portal venous phase contrast-enhanced CT scans were obtained in helical mode 25 and 65 sec after the initiation of infusion of a 4-5 mL per sec injection of 150 mL of nonionic IV contrast material (ioversol 68%, Optiray 320; Mallinckrodt), respectively. Contrast material was administered IV via a power injector (Medrad). All scans were performed using 7-8 mm collimation, 220 mA, and 120 kVp. The pitch (1-1.5) was adjusted as necessary to allow a single helical acquisition through the entire liver in each vascular phase. The two patients who had MRI scans were imaged on a 1.5-T clinical magnet (Signa, software version 5.45, GE Healthcare) using a body coil. Unenhanced T1-weighted gradient-echo (TR/TE 500/15, 20° flip angle) and T2-weighted fast spin-echo (TR/TE 3,200/102) pulse sequences were obtained with 8-mm slice thickness and a 2-mm gap. Dynamic contrast-enhanced T1-weighted fast spoiled gradient-echo (TR/TE 140/2.1, 30° flip angle) images were obtained at the initiation of injection of IV gadodiamide (20 mL Omniscan IV 287 mg/mL, Amersham Health) and continued for 2 min.
Ablation Equipment, Procedure, and Medications
Ablations were performed percutaneously under sonographic guidance using
three commercially available radiofrequency ablation devices (Star-burst
electrode and model 500LA generator, RITA Medical Systems; CT2020, CT2030, and
CTC2025 electrodes and model CC-1 generator, Radionics; and 3.5/15 electrode
and RF2000 generator, Radiotherapeutics). Forty ablation sessions were
performed with the Radionics device, eight with the RITA device, and two with
the Radiotherapeutics device. For all devices, the skin at the sites of the
planned needle puncture(s) was anesthetized with 1% Xylocaine (lidocaine HCl,
AstraZeneca). The anesthesiologist or nurse anesthetist administered an IV
sedative of Diprivan (propofol, AstraZeneca) or Ultiva (remifentanil HCl,
Glaxo Wellcome) by drip infusion throughout the duration of the procedure. All
ablations were performed using the manufacturer's recommended ablation
protocols. The number of ablations performed per tumor and per patient was
determined by the size and number of tumors being treated. All needle
electrode tracks in the liver were cauterized before withdrawing the needle
electrode from the liver. Immediately after the procedure, Anzemet (dolasetron
mesylate, Hoechst-Marion Roussel) and morphine were administered IV to control
acute pain and nausea. The patients were also given oral Vicodin (hydrocodone
bitartrate and acetaminophen, Knoll Laboratories) to control subacute
postablation pain [15].
Postablation Evaluation
Within 1 hr of the procedure, all patients had repeat blood chemistries and
liver enzymes drawn. Within 4 hr after ablation, CT or MRI was performed with
the same imaging protocols used before ablation. Acute symptoms were recorded
during the patient's 6-hr hospital stay after the procedure. After discharge,
the patients were followed by daily telephone interviews for 3 weeks with a
standardized questionnaire (Fig.
1) completed to assess for symptoms such as fever, nausea, chills,
arthralgias, malaise, and pain.
|
)r3. In patients with more than one
tumor, the volumes of the tumors were summed to obtain total tumor volume.
Preablation measurements of total liver volume were made from portal venous
phase CT scans and T1-weighted MRI scans by summing the area of the liver on
all consecutive images and then multiplying by a correction factor that
adjusted for slice thickness, pitch, and/or gap
[16,
17]. Postablation measurements
of the tumor ablation volumes were made from portal venous phase CT and
T2-weighted MRI scans using the same method as for preablation tumor volumes.
Postablation reactive peritumoral hyperemia was excluded from the tumor
measurements.
Data Analysis
Comparisons of the presence or absence of symptoms were performed for pre-
and postablation laboratory test values, liver volumes, pre- and postablation
tumor volumes, and pre- and postablation tumor volumes expressed as a
percentage of liver volume. Also compared were the changes from pre- to
postablation for each measure. All comparisons were performed using unpaired
Student's t tests, with p < 0.01 considered significant.
Results were reported using the mean ± standard error of the mean (SEM)
for each group. If a comparison indicated that a measure had a mean value for
patients who developed postablation symptoms that was significantly different
from the mean value for patients who remained asymptomatic, that measure was
investigated further to determine three meaningful critical values defining
minimal, intermediate, and maximal risk exposure. Epidemiologic measures were
then obtained for each definition of risk, and receiver operating
characteristic (ROC) curves were plotted. Chi-square tests were performed to
determine if the areas under the ROC curves were greater than 0.5 (with
p < 0.01 considered significant) to ascertain whether the set of
risk exposures for a measure was an important predictor of postablation
symptom development by patients. Spearman's correlations were performed among
the corresponding (preablation, postablation, or change score) measures
identified as risk factors. If measures had significant correlation (rho >
0.5, p < 0.001), then they were assumed to be redundant risk
factors; otherwise, binary logistic regression was performed to determine if
the prediction of delayed symptoms was enhanced by combining the uncorrelated
measures already shown to be risk factors. Statistical analysis was performed
using software (SAS Institute), and ROC curves were plotted using a
Statistical Package for the Social Sciences (SPSS).
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Postablation symptoms occurred in 14 of 39 (36%) patients after 17 of 50 (34%) ablation sessions. Liver volumes ranged from 854 cm3 to 2,315 cm3. Preablation tumor volumes ranged from 1.06 cm3 to 648.5 cm3, or 0.09% to 44.4% of liver volumes. Postablation tumor/ablation volumes ranged from 7.95 cm3 to 884.35 cm3, or 0.51% to 60.6% of liver volumes. The pre- to postablation increase in tumor/ablation volumes ranged from 0.4 cm3 to 406.3 cm3, or 0.0% to 30.3% of liver volume. Significant differences between symptomatic and asymptomatic patients were observed for preablation tumor volume in cm3 (symptomatic = 187.7 ± 49.6, asymptomatic = 35.7 ± 7.8; p < 0.01), preablation tumor volume as a percentage of liver volume (13.54 ± 3.57 and 2.75 ± 0.61, respectively; p < 0.01), ablated tissue volume in cm3 (359.8 ± 65.3 and 111.7 ± 18.1, respectively; p < 0.005), ablated tissue volume as a percentage of liver volume (25.44 ± 4.99 and 8.44 ± 1.51, respectively, p < 0.005), difference between tumor and ablated tissue volumes in cm3 (172.1 ± 30.2 and 76.0 ± 15.0, respectively; p < 0.01), difference between tumor and ablated tissue volumes as a percentage of liver volume (11.90 ± 2.26 and 5.69 ± 1.19, respectively; p < 0.01), but not preablation liver volume (1,507 ± 72.9 and 1,463 ± 67.3, respectively; p > 0.60).
Among the laboratory values evaluated, significant pre- to postablation increases were observed for WBC counts (p < 0.001), AST (p < 0.001), ALT (p < 0.005), neutrophils (p < 0.001), and bilirubin (p < 0.001), while significant pre- to postablation decreases were observed for RBC counts (p < 0.010), albumin (p < 0.005), total protein (p < 0.001), calcium (p < 0.001), eosinophils (p < 0.010), monocytes (p < 0.005), and lymphocytes (p < 0.001). However, the only pre- or postablation laboratory value for which a significant difference between symptomatic and asymptomatic patients was observed was postablation AST in IU/L (symptomatic = 517.8 ± 100.8, asymptomatic = 250.8 ± 41.3, p < 0.01). Likewise, the difference between the pre- and postablation AST levels was the only measure among laboratory values that was significantly different for symptomatic versus asymptomatic patients (463.5 ± 98.7 IU/L and 195.8 ± 42.6 IU/L, respectively; p < 0.01).
The results of our analysis of the risk for postablation symptoms relative to the measured laboratory tests and the liver, tumor, and ablation volumes are reported in Table 1 and Figs. 2, 3, 4, 5, 6. The thresholds for minimal and maximal risk are particularly interesting as they may have clinical utility in predicting which patients will develop postablation symptoms. Patients with a preablation average tumor diameter less than or equal to 3.25 cm, a postablation tumor/ablation average diameter less than or equal to 5.25 cm, a difference between pre- to postablation tumor/ablation volumes of less than or equal to 25 cm3, or a postablation AST level less than or equal to 150 IU/L were unlikely to develop postablation symptoms (negative predictive value 80-85.7%). However, patients with a difference between pre- to postablation tumor/ablation volumes greater than 225 cm3, a postablation AST level greater than 500 IU/L, or a pre- to postablation increase in AST greater than 450 IU/L were highly likely to develop postablation symptoms (specificity 93-94%, positive predictive value 75-77.8%). Lastly, patients who had a total tumor volume that was greater than 250 cm3 (average diameter > 7.75 cm) or exceeded 20% of the volume of the liver, or a total postablation tumor/ablation volume that was greater than 450 cm3 (average diameter > 9.5 cm) or exceeded 40% of the volume of the liver, all developed postablation symptoms.
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All the pre- and postablation tumor/ablation volume measurements individually and as a percentage of liver volume, and the difference between the pre- and postablation tumor/ablation volumes individually and as a percentage of liver volume, were significantly correlated (rho = 0.975-0.986, p < 0.001). Likewise, the postablation AST and the pre- to postablation increase in AST were significantly correlated with the two measures of ablated tissue volume and both measures of differences between tumor volume and postablation tumor/ablation volume, rho > 0.55, p < 0.001; and rho > 0.60, p < 0.001, respectively. Because of the high correlations among the identified risk factors, they were assumed to be redundant, so a binary logistic regression combining each of these factors was not performed.
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To our knowledge, no prospective study of a postablation syndrome occurring after radiofrequency ablation of hepatic tumors has been reported; however, prior reports on clinical efficacy of radiofrequency ablation of hepatic tumors have mentioned some side effects in patients treated with the technique. The most common observation has been transient elevation of liver transaminases. In three studies, all patients had a two- to four-fold increase in transaminases that returned to normal between 1 and 4 weeks after ablation [6-8]. Postablation fever has been reported in fewer than 10 patients of a total of 413 patients in five studies [9-13]. Persistent pain after ablation was reported in approximately 17 of 268 patients treated in five studies [4, 8, 9, 12, 14]. In only one study were patients reported to have experienced flulike symptoms after ablation. Iannitti et al. [13] report that several of their 123 patients who underwent radiofrequency ablation of hepatic tumors had flulike symptoms known as postablation syndrome that always resolved within 2 weeks and were treated with supportive care.
In our study we identified a postablation syndrome that occurs in approximately one third of patients after percutaneous radiofrequency ablation of primary or metastatic malignant hepatic tumors. The signs and symptoms of the syndrome are similar to those reported for other ablative techniques. The most common symptoms are fever and malaise, with chills, pain, and nausea occurring less frequently. On average, the symptoms usually present around 3 days after the ablation session and last approximately 5 days. Patients have likened the side effects to those experienced with a bout of the flu. Clinically, the most concerning of the symptoms is fever, as it may lead to the assumption that the patient is septic. Postablation febrile episodes typically produced temperatures between 99°F and 102°F, with a mean temperature of 101°F. It is important to note that none of our patients developed sepsis during the 3-week period that they were followed for this study. Only one of the 16 patients who became febrile received antibiotics, and the blood cultures drawn before administering the antibiotics were negative for infection.
In our analysis of the relationship of the postablation symptoms to laboratory studies, tumor volumes, volume of tissue ablated, and the liver volumes, we found that before ablation, the only significant predictor was tumor volume (p < 0.010); after ablation, the volume of tissue ablated and the AST level were significant (and correlated) predictors (p < 0.010). Among the pre- to postablation change measures, the only significant (and correlated) predictors were the difference between tumor volume and the volume of tissue ablated and the increase in AST (p < 0.005). Furthermore, we found several thresholds that should be clinically useful: Patients undergoing ablation of a single hepatic tumor less than 3.25 cm in diameter or patients with a postablation AST level less than 150 IU/L are unlikely to experience postablation symptoms; patients undergoing radiofrequency ablation of tumors greater than 7.75 cm experience postablation symptoms; and patients with postablation AST levels greater than 350 IU/L or 500 IU/L have an intermediate and high risk of experiencing postablation symptoms, respectively.
In conclusion, postablation syndrome is a common phenomenon after radiofrequency ablation of primary or metastatic malignant hepatic tumors. In our study it occurred in approximately one third of patients, consisted of transient flulike symptoms (e.g., fever, malaise, chills, pain, and nausea), and was related to the volume of tissue ablated. Useful predictors to determine which patients may develop postablation symptoms include the size of the tumor(s) treated and the postablation AST levels. Familiarity with the existence and spectrum of postablation syndrome should facilitate appropriate management of affected patients.
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